Direct catalytic asymmetric aldol reactions of thioamides: Toward a stereocontrolled synthesis of 1,3-polyols

Article abstract of DOI:10.1021/ja909758e

(Chemical Equation Presented) A direct catalytic asymmetric aldol reaction of thioamides with a soft Lewis acid/hard Bronsted base cooperative catalytic system comprising (R,R)-Ph-BPE/[Cu(CH₃CN) ₄]PF₆/LiOAr is described. H

Full text of DOI:10.1021/ja909758e

Published on Web 12/08/2009
Direct Catalytic Asymmetric Aldol Reactions of Thioamides: Toward a
Stereocontrolled Synthesis of 1,3-Polyols
Mitsutaka Iwata, Ryo Yazaki, Yuta Suzuki, Naoya Kumagai,* and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, 7-3-1 Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
Received November 17, 2009; E-mail: mshibasa@mol.f.u-tokyo.ac.jp, nkumagai@mol.f.u-tokyo.ac.jp
Scheme 1. Biosynthetic and Direct Aldol Approaches to
The 1,3-polyol system is a frequently occurring structural
motif found in a plethora of biologically active natural products,
most prominently represented by the macrolide antibiotics.1 The
importance of this particular class of compounds has prompted
chemists to pursue efficient methodologies for the stereocon-
trolled synthesis of 1,3-oriented hydroxy group arrays,2 but there
remains much room for the development of a general and rapid
protocol via catalytic asymmetric C-C bond formation.2,3 In
nature, multifunctional enzymes called polyketide synthases are
harnessed to enable efficient, iterative elongation of a thioester-
activated C2 unit through a decarboxylative Claisen condensation
coupled with an enzymatic stereoselective reduction of ketones
to provide 1,3-polyol arrays (Scheme 1a).1,4 Herein, we report
a comparably efficient approach using thioacetamide 1 as the
C2 unit, which was iteratively installed via a direct catalytic
asymmetric aldol reaction in conjunction with the construction
of enantioenriched secondary alcohols by catalyst-controlled
stereoselection (Scheme 1b).
1,3-Polyols
Table 1. Direct Catalytic Asymmetric Aldol Reaction of Thioamide
1aa
The direct catalytic asymmetric aldol reaction has gained
increasing attention as an atom-economical proton-transfer C-C
bond-forming process,5,6 where an active enolate is catalytically
generated in situ and integrated into the subsequent enantioselective
addition to aldehydes. Whereas recent advances in this field have
allowed for the implementation of various aldol donors in this
efficient process, those in the carboxylic acid oxidation state have
yet to be exploited because of the intrinsic difficulty of deprotonative
activation.7-9 To consolidate the iterative direct aldol reaction
outlined in Scheme 1b while allowing further elaboration of the
aldol products, an aldol donor in the carboxylic acid oxidation state
is desirable.10 We envisioned the use of thioamides as the C2 aldol
donor for this purpose,11 as these would be chemoselectively
activated to generate thioamide enolates under soft Lewis acid/
hard Brønsted base cooperative catalysis.
We began this study with the reaction of N,N-diallylthioacetamide
(1a) and isobutyraldehyde (2a) in THF at -20 °C in the presence
of 10 mol % (R,R)-Ph-BPE/[Cu(CH3CN)4]PF6/Li(OC6H4-o-OMe)
catalyst (Table 1, entry 1), which is effective in direct Mannich-
type reactions of thioamides.12 The reaction, however, was very
sluggish, and the desired product 3aa was obtained in only 5%
yield after 60 h, albeit with encouraging enantioselectivity (79%
ee). Thin-layer chromatography, NMR, and electrospray ionization
mass spectrometry analyses indicated that 3aa was tightly bound
to the (R,R)-Ph-BPE/Cu catalyst, suggesting that the catalytic cycle
was arrested by product inhibition.13 The addition of pyridine
somewhat improved the yield without affecting the enantioselec-
tivity, likely because of the competitive coordination of the pyridine
to copper to liberate the product (entries 2 and 3). The use of a
Lewis basic solvent effectively circumvented the product inhibition
to afford 3aa in good yield, despite concomitant ꢀ-elimination
(entries 4-6), which was mostly prevented by decreasing the
a 1a, 0.24 mmol; 2a, 0.2 mmol. b Determined by 1H NMR analysis.
Yields of dehydrated products are provided in parentheses.
temperature to -60 °C (entry 7). Use of the stronger Brønsted base
2,2,5,7,8-pentamethylchromanol lithium salt (4) compensated for
the reduced catalytic activity at the lower temperature, affording
3aa in 91% yield and 95% ee (entry 8).13 The reaction reached
completion with as little as 3 mol % catalyst (entry 9).
The scope of the direct catalytic asymmetric aldol reaction was
then examined (Table 2).14 Commercially available thioamide 1b
gave better enantioselectivity in the reaction with 2a, although with
a marginal loss in the chemical yield (entries 1 and 2). Other
branched aldehydes 2b-d were well-suited for the present catalytic
system and exhibited high enantioselectivity (entries 3-5). Non-
branched aldehydes 2e-i, which are susceptible to self-condensation
under basic conditions, afforded the desired products without the
formation of self-aldols (entries 6-10). An ester functionality was
also tolerated in the reaction of 2i, confirming the mild basic
conditions (entry 10). The aldol reaction of 2a in the presence of
acetophenone, which is more prone to form an enolate than 1a in
terms of the pKa of the R-proton, afforded only 3aa, further
highlighting the highly chemoselective nature of the present catalytic
9
18244 J. AM. CHEM. SOC. 2009, 131, 18244–18245
10.1021/ja909758e  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Substrate Scope of the Direct Catalytic Asymmetric Aldol
Reaction of Thioamides 1a
of thioamide regenerates the aldehyde functionality, and a second
direct aldol reaction proceeds stereoselectively in a catalyst-
controlled manner. Future work will be dedicated to applying the
present protocol to the asymmetric synthesis of natural products
bearing a 1,3-polyol motif.
Acknowledgment. Financial support was provided by a Grant-
in-Aid for Scientific Research (S) and the Sumitomo Foundation.
R.Y. thanks JSPS for a predoctoral fellowship.
Supporting Information Available: Experimental details and
characterization of new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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Having developed the direct catalytic asymmetric aldol reaction
of thioamides, we applied the protocol to 1,3-diol synthesis (Scheme
2). TBS protection followed by reduction of the thioamide
functionality with the Schwartz reagent converted 3ba to aldehyde
5 in 82% yield (two steps),15 and 5 was then subjected to another
direct aldol reaction with either the R- or S-configured catalyst.
The reaction proceeded stereoselectively to afford diol (3S,5R)-6
or (3R,5R)-6, respectively, indicating that the catalyst largely
controlled the newly formed stereogenic center.16
(7) There are numerous examples of direct aldol reactions using aldol donors
bearing electron-withdrawing R-substituents that are readily enolized under
mild basic conditions.
(8) Direct catalytic asymmetric aldol(-type) reactions using aldol donors in
the carboxylic acid oxidation state without electron-withdrawing R-sub-
stituents: Alkylnitriles: (a) Suto, Y.; Tsuji, R.; Kanai, M.; Shibasaki, M.
Org. Lett. 2005, 7, 3757. Activated amides: (b) Saito, S.; Kobayashi, S.
J. Am. Chem. Soc. 2006, 128, 8704. ꢀ,γ-Unsaturated esters: (c) Yamaguchi,
A.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 10842.
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the use of a stoichiometric amount of silylating reagent was essential: Evans,
D. A.; Downey, C. W.; Hubbs, J. L. J. Am. Chem. Soc. 2003, 125, 8706.
(10) The cross-aldol reaction of aldehydes via asymmetric organocatalysis
provides a useful methodology for the synthesis of polyols and sugars.
Selected examples: (a) Northrup, A. B.; MacMillan, D. W. C. Science 2004,
305, 1752. (b) Co´rdova, A.; Ibrahem, I.; Casas, J.; Sunde´n, H.; Engqvist,
M.; Reyes, E. Chem.sEur. J. 2005, 11, 4772. (c) Markert, M.; Scheffler,
U.; Mahrwald, R. J. Am. Chem. Soc. 2009, 131, 16642. Also see ref 6b-
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as the nucleophile, see: (d) Yang, J. W.; Chandler, C.; Stadler, M.; Kampen,
D.; List, B. Nature 2008, 452, 453. (e) Hayashi, Y.; Itoh, T.; Aratake, S.;
Ishikawa, H. Angew. Chem., Int. Ed. 2008, 47, 2082.
Scheme 2. Catalyst-Controlled Direct Catalytic Asymmetric Aldol
Reaction for the Synthesis of 1,3-Diolsa
(11) Asymmetric aldol reaction of thioamides with a stoichiometric chiral
source: (a) Cinquini, M.; Manfredi, A.; Molinari, H.; Restelli, A. Tetra-
hedron 1985, 41, 4929. (b) Iwasawa, N.; Yura, T.; Mukaiyama, T.
Tetrahedron 1989, 45, 1197.
a Conditions: (a) TBSOTf, 2,6-lutidine, CH2Cl2; (b) Cp2Zr(H)Cl, toluene,
rt; (c) 1b, [Cu(CH3CN)4]PF6/(R,R)-Ph-BPE/4 (10 mol %), DMF, -60 °C,
40 h; (d) 1b, [Cu(CH3CN)4]PF6/(S,S)-Ph-BPE/4 (10 mol %), DMF, -60
°C, 40 h.
(12) Suzuki, Y.; Yazaki, R.; Kumagai, N.; Shibasaki, M. Angew. Chem., Int.
Ed. 2009, 48, 5026.
(13) See the Supporting Information.
(14) Aromatic aldehydes were more reactive in this system, leading to retro-
aldol reaction and dehydration of the aldol product (e.g., benzaldehyde:
66% yield, 72% ee). Further investigations are currently underway.
(15) Spletstoser, J. T.; White, J. M.; Tunoori, A. R.; Georg, G. I. J. Am. Chem.
Soc. 2007, 129, 3408.
In summary, we have documented a direct catalytic asymmetric
aldol reaction of thioamides. The soft Lewis acid/hard Brønsted
basecooperativecatalysisexertedby(R,R)-Ph-BPE/[Cu(CH3CN)4]PF6/
4 enables highly chemoselective deprotonative activation of thioa-
mides over aldehyde and ketone functionalities. Facile reduction
(16) Recent selected examples of catalyst-controlled diastereoselectivity: (a)
Balskus, E. P.; Jacobsen, E. N. Science 2007, 317, 1736. (b) Han, S. B.;
Kong, J. R.; Krische, M. J. Org. Lett. 2008, 10, 4133.
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